September 28, 2013

EMBO 2013: Tales from the crypt

The Keynote lecture on Day 3 was from Hans Clevers,
who is director of, and runs a lab at, the Hubrecht Institute in Utrecht and is
also President of the Royal Netherlands Academy of Arts and Sciences. Clevers gave an amazing presentation of his
lab’s work on intestinal stem cells that was accompanied by movie-quality
animations that really helped visualize the significance of his results. The intestinal epithelium has very
interesting morphology: we all know about villi and their importance in
digestion but in between the villi are ‘crypts’, narrow tunnels at the bottom
of which lie the intestine’s stem cells.
Each crypt makes 200 cells/day so this is a very active stem cell
compartment. It has to be because the cells of this epithelium must be replaced
every 4-5 days. Defining the stem cell
population in the crypt has been challenging and the subject of much
controversy. Clevers’ lab has made great
strides in this area using sophisticated genetic engineering techniques that
allow them to mark and manipulate single cells in the mouse intestine (for a great review
on lineage tracing in epithelia, click here).
They identified a population of columnar epithelial cells at the bottom
of the crypt, positive for the marker Lgr5 (see figure), that give rise to all the cell
types of the intestine.
The surrounding Paneth cells serve as the niche
for these stem cells.
They isolated these Lgr5-positive cells, figured out the conditions to grow
them in vitro and found, amazingly, that these single cells could grow into
‘miniguts’ with the right tissue morphology. They then introduced these miniguts into mice
and found that they attached only to damaged epithelia (which occurs for
example with ulcers) and sealed the lesion, without any occurrence of adenomas. These miniguts have great therapeutic
potential; Clevers showed that they can
grow miniguts from intestinal stem cells isolated through patient biopsies and
test the efficacy of drugs on this pseudotissue. For example, they have used the miniguts to
monitor CFTR channel function and test cystic fibrosis drugs. I found this to be a very inspiring
talk: this lab came to this field
through a long standing interest in Wnt signaling and now are actively
exploring the therapeutic potential of their findings. It really was a tour-de-force example of how
basic cell biology can lead to more clinical applications.

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